Remission of type 2 diabetes in a hypogonadal man after long-term testosterone therapy

The number of patients with type 2 diabetes is increasing rapidly in both developed and developing countries around the world. The emerging pandemic is driven by the combined effects of population ageing, rising levels of obesity, sedentary lifestyle and unhealthy food habits.1,2 The prevalence of type 2 diabetes is around 12% in Western countries, and rises to 25% among those aged >65 years.3

Approximately half of diabetic men have testosterone deficiency.4 Considering that testosterone is a potent metabolic hormone 5,6, it is not surprising that studies unequivocally show that testosterone deficiency impairs insulin sensitivity and increases blood glucose and HbA1c, and risk of developing type 2 diabetes.7,8 Hence, treating diabetic men who are hypogonadal with only diabetes medications is likely only going to control glycemia at best. Remission of diabetes does typically not occur with diabetes medications only.

A growing number of studies have shown that testosterone therapy increases insulin sensitivity and reduces levels of blood glucose and HbA1c.7-10 However, whether testosterone therapy can help diabetic men achieve remission has not been thoroughly studied. Here we report the results from a notable case study of remission of type 2 diabetes in a hypogonadal man under long-term testosterone therapy, recently published in the journal of Endocrinology Diabetes & Metabolism Case Reports.11

Key Points

Hypogonadism is common in men with type 2 diabetes.

Men with diabetes and/or pronounced abdominal fat deposition should be evaluated for testosterone deficiency and have their testosterone levels checked.

During long-term testosterone treatment, blood glucose, HbA1c, and insulin resistance return to normal range, and complete remission of diabetes can be achieved (return to non-diabetic state without diabetes medications).

What is known about type 2 diabetes and testosterone

Among men with type 2 diabetes, the prevalence of testosterone deficiency ranges from 25% to 43% using the total testosterone cut-off <10.4mmol/L (300 ng/dL).12-16 With a cut-off of <12 nmol/L (346 ng/dL), the prevalence of testosterone deficiency is 45%.17 Even after adjusting for age and BMI, the prevalence of subnormal free testosterone levels (<50 pg/mL or 144 pmol/L) in men with type 2 diabetes is higher than in men without (45% versus 33%).4 In diabetic men who are also obese (BMI >30) the prevalence of testosterone deficiency is 51%. 4

Consequently, all major clinical practice guidelines on hypogonadism recommend that testosterone levels are measured in men who are obese and/or have type 2 diabetes.18-21 The 2016 American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) Clinical Practice Guidelines for Comprehensive Medical Care of Patients with Obesity point out that there are strong associations between obesity, hypogonadism, and cardiometabolic disease, and that measurement of testosterone levels should be included in the diagnostic evaluation of metabolic syndrome and type 2 diabetes.22 The AACE/ACE clinical practice guidelines recommend that all men with type 2 diabetes, or all men who have an increased waist circumference (≥102 cm) or who are obese (BMI ≥30 kg/m2) should be assessed for hypogonadism by history and physical examination and measurement of testosterone levels.22 The International Society for Sexual Medicine's Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men even recommends systematic screening for testosterone deficiency in men with obesity, type 2 diabetes or the metabolic syndrome.20

Since diabetes is a metabolic disease that can be improved by diet and exercise, it is reasonable to expect that lifestyle interventions could lead to remission of type 2 diabetes. However, this is extremely rare. A study reported that only 0.8% of patients experienced any level of remission during one year.23 The chance of dying (1.7% of the patient group died) was found to be higher than the chance of any remission.23

One reason contributing to the difficulty achieving remission of diabetes in men could be testosterone deficiency. Whether treatment of underlying testosterone deficiency can help men achieve remission of type 2 diabetes has not, until recently, been specifically investigated.

What this study adds

In the present case study, a 63-year-old man suffering from recurrent prostatitis and lower urinary tract symptoms (LUTS), combined with loss of libido and erectile dysfunction was referred to a urologist. At the time of referral, the obese patient (BMI: 37.1 kg/m2) had been diagnosed with type 2 diabetes 4 years ago and presented with an HbA1c of 9.4%.

He had been on metformin for 4 years and on insulin treatment for 2 years at 22 IU per day. Since starting insulin, the patient had gained 5 kg. Doctors’ instructions to lose weight by diet and exercise had been unsuccessful. Comorbidities comprised dyslipidemia, mild hypertension and coronary artery disease.

Outcome and follow-up

The patient was routinely monitored at 3-month intervals for 10 years. Testosterone increased from 10 nmol/L (288 ng/dL) to approximately 17 nmol/L (490 ng/dL) and remained in the normal range during the observation period. During testosterone therapy, the patient continuously lost weight; at treatment year 10, the patient had achieved a weight loss of 24 kg (20.2%) and reduction in waist circumference of 12 cm (Figure 1). BMI dropped to 29.6 kg/m2 (Figure 2).

Critical laboratory values related to diabetes and other comorbidities substantially improved and even returned to normal range. Right from the beginning of testosterone therapy, fasting glucose declined and remained below 6 mmol/L (108 mg/dL) from the 3rd year onward. A progressive decrease of insulin resistance and HbA1c occurred, which allowed for a gradual reduction in insulin dose: from 22 IU/day to 18 IU/day at the end of year 1, to 14 IU/day at 30 months and to 12 IU/day in the 6th year. Finally, with an HbA1c value of 6.7% achieved in year 7, insulin use was discontinued. In the following time, without further administration of insulin, HbA1c further decreased to 6.1% (Figure 3) and HOMA-IR to 2.8 in year 8 (Figure 4). Metformin was discontinued in year 10.

Libido was assessed as part of the Aging Males’ Symptoms (AMS) scale, which improved both in total and in every single item. Erectile function was assessed by the International Index of Erectile Function – Erectile Function domain (IIEF-EF). At baseline, the patient had mild erectile dysfunction, which improved to “no erectile dysfunction” status that was maintained over the entire observation time despite the fact that the patient’s age increased by 10 years.

Figure 4: Reduction in HOMA-IR from 11.7 at baseline to 2.8 in month 102 (8.5 years).

Figure 5: Increase in HDL and reduction in LDL over time. HDL/LDL ratio improved from 3.3 at baseline to 1.4 in month 114 (9.5 years).

Commentary

Disease remission is defined as abatement or disappearance of the signs and symptoms of a disease, with the possibility of recurrence of the disease.24 The American Diabetes Association defines remission as achieving glycemia below the diabetic range in the absence of active pharmacologic (anti-hyperglycemic medications, immunosuppressive medications) or surgical (ongoing procedures such as repeated replacements of endoluminal devices) therapy. A remission can be partial or complete. Partial remission is sub-diabetic hyperglycemia (HbA1C not diagnostic of diabetes [<6.5%], fasting glucose 100–125 mg/dL [5.6–6.9 mmol/L]) of at least 1 year’s duration in the absence of active pharmacologic therapy or ongoing procedures. Complete remission is a return to “normal” measures of glucose metabolism (HbA1C in the normal range, fasting glucose <100 mg/dL [5.6 mmol/L]) of at least 1 year’s duration in the absence of active pharmacologic therapy or ongoing procedures.

Remission of type 2 diabetes could be attained with lifestyle interventions targeting regular exercise and/or healthy eating, or bariatric/metabolic surgery. Nondiabetic glycemia resulting from ongoing medications or repeated procedures (such as in the dynamic phase of band adjustment after laparoscopic gastric banding) would not meet the definition of remission, as these interventions are considered treatment. The case report presented here shows that testosterone therapy in hypogonadal men qualifies for the definition of diabetes remission.

While larger studies on the effects of testosterone therapy on remission of diabetes are lacking, it is interesting to note that testosterone therapy with testosterone undecanoate injections for up to 9 years completely prevents progression of prediabetes to frank type 2 diabetes.25 Another study shows that most hypogonadal men with type 2 diabetes achieve HbA1c targets when treated with testosterone undecanoate injections for up to 12 years.26 These exceptionally long-term studies support the use of testosterone therapy in hypogonadal men with metabolic derangements.

Testosterone treatment has beneficial effects on measures of obesity that are partially explained by both direct metabolic actions on adipose and muscle tissues, and also potentially by increasing motivation, vigour and energy allowing obese individuals to engage in more active lifestyles.6 Previous studies have shown that testosterone therapy consistently improves mood and feelings of energy, and reduces fatigue.27-32 Support for this comes from experimental data showing that testosterone boosts physical activity via a central action on dopaminergic pathways.33 This in turn may bolster motivation and the ability to adhere to diet and exercise programs which is critical for achievement of remission of diabetes.34-36 Especially remarkable is the maintainable weight loss during testosterone therapy, as shown in long-term “real life” observational studies with follow-up data for up to 8 years.37-40 As in the present case report, these studies showed sustained weight loss during testosterone therapy, resulting in a significant improvement in blood glucose, insulin sensitivity, lipid profile, inflammatory markers and blood pressure.37-40

It was previously shown that testosterone therapy is particularly beneficial in obese men with type 2 diabetes 39 but when analyzing 6-year data there was not any case with complete remission. This underscores the importance of long-term treatment with testosterone, and suggests that it takes many years for metabolic disease states to normalize. Indeed, an analysis of the time course for the onset of metabolic effects shows that full expression of the benefits of testosterone therapy takes several years to manifest.41

Patients often wonder how long they need to be on testosterone treatment. Several studies show that the beneficial effects of testosterone therapy are not sustained after cessation of treatment.42-44 While young obese men who successfully lose excess body fat and reach – and maintain – a non-obese state may get their endogenous testosterone production restored, for most men testosterone therapy will likely be a lifelong treatment. It is well established that hypogonadal men, in particular those with excess body fat, enlarged waist circumference, and related metabolic diseases (metabolic syndrome an type 2 diabetes) benefit from testosterone therapy,6,7,45 and that non-treatment of these men severely worsens their health status over time.46,47